June 23, 2015

As most of you may know, Lantus, the most commonly prescribed basal insulin, saw its patent protection expire in February of this year. Several new competitors in the basal insulin niche are waiting in the wings, hoping to siphon off some of the $9 billion a year the French firm Sanofi has been earning from Lantus.

Two brand new basal insulins currently on deck are Novo Nordisk's Tresiba and a peglispro, from Lilly. Tresiba has been already available in Europe since 2013 but is not approved in the U.S.. It achieves similar blood sugar results as Lantus while claiming to produce fewer nighttime hypos.

Peglispro is not yet approved anywhere yet, and its approval appears to be getting delayed due to some troubling signs found in clinical trial data that suggest it may harm the liver and that it may cause more severe hypos than existing basal insulins.

Besides these new analog insulins, there is another kind of competitor ready to take away Lantus' market share: biosimilars. These are protein molecules that claim to be similar in action, though not identical in structure, to another drug. They are as close as we can get to a generic product with hormones like insulin. Lilly, in partnership with Boehringer Ingelheim, has already received approval to market its biosimilar insulin glargine, Basaglar in Europe and has tentative FDA approval to market it in the U.S. though because of a patent dispute with Sanofi, it can't bring Basaglar to market in the U.S. until mid 2016. .

What is Toujeo?
To defend itself against this dramatic ramp up in competition, Sanofi has come out with its own "new" basal insulin, which it is calling Toujeo. However, Toujeo is not really a new insulin, as it uses the same molecule, insulin glargine, as Lantus. All that is different is that it now comes in a more highly concentrated form. Regular Lantus is a U100 insulin, which means there are 100 units of the insulin in every 1 milliliter of solution. Toujeo, in contrast, is a U300 insulin. So there are 300 units in every milliliter. This means you inject a smaller amount of fluid to get the dose of insulin you need and may change the speed with which the insulin is absorbed and how long it stays active.

This may be handy for people with Type 2 who use very large doses of insulin. However, it may not be easier on their wallets, since to keep people from giving themselves three times as much insulin as they need, Sanofi will only market Toujeo in pens, not the cheaper vials. The reason for this is that you would need to use a special U300 calibrated syringe to correctly dose U300 insulin. This would make possible terrible dosing mistakes, since someone accidentally using a syringe calibrated for U100 insulin with Toujeo would end up injecting three times as much Toujeo as they would need, a great way to cause a potentially fatal hypo. So to eliminate this possibility Toujeo will only be made available in pens calibrated to dispense the expected dose.

If you are happy with Lantus, there is nothing to suggest that you need to switch to Toujeo. Though you can expect to see a heavy advertising campaign intended to make you think you should. Sanofi had hoped to market Toujeo in the U.S. with the claim that it caused fewer hypos than Lantus, but the FDA did not feel that the data they submitted proved this. So the only real selling proposition for Toujeo is that it makes dosing very large doses easier.

However, the European regulators did approve the claim that Toujeo caused fewer hypos than Lantus, so you can pretty much take your choice about who to believe. This kind of disagreement suggests to me that the difference in hypos between Lantus and Levemir is small enough that it could easily be due to the drug company tweaking the way it designed its comparison study and analyzed its data.

What About Tresiba?
If you are in Europe and want a more highly concentrated basal insulin, you can also get a pen version of Novo Nordisk's Tresiba that is U200, which allows you to inject 160 units in a single shot. Tresiba also comes in a U100 format.

Tresiba, unlike Toujeo is a truly new analog insulin molecule, insulin degludec. Because it is new, and like all analog insulins is not quite identical to human insulin, its long term side effects have yet to be fully understood. This is why they F.D.A. has delayed approving it, out of concern that it might have a different profile in regard to cardiovascular effects.

The European label for Tresiba supports its claim to dramatically lower the incidence of nighttime hypos, which might be a strong selling point once it does get approved in the us.

People with diabetes have to hope that this injection of competition into the basal market will result in prices dropping to the benefit of consumers. But in the strange Alice in Wonderland world of Big Pharma this is far from guaranteed. Worst case, some people fear, cheaper biosimilars that do not actually perform as well as branded basal insulins may be imposed on us by insurers who will treat them just like any other generic drug and refuse to pay the premium for a branded insulin if a biosimilar exists. If as some argue small chemical differences in these biosimilars keep them from actually duplicating the effect of the molecule they mimic, this could be a big problem going forward. Best case, some of the newer basals may perform better and insurers may cover them because they prevent those serious hypos. We'll know how it works out in another couple years.

As soon as Dr. Butler's study came out, there was a rush to publish studies that supposedly refute it, funded, not so surprisingly by the companies who are earning billions of dollars from these highly profitable drugs.

This study claimed to find no sign of pancreatic disease with Onglyza.

This week, a larger, much more high profile study of Januvia was published in the New England Journal of Medicine in June of 2015. It was presented at the 2015 ADA conference which took place this past weekend and is being treated as if it removes all barriers to prescribing Januvia as it has supposedly dismissed all safety concerns about the drug.

Though the focus of the study was on cardiovascular outcomes, it was also reported as stating that there was no sign of more pancreatitis or pancreatic cancer in the group that took Januvia. This, apparently, is being interpreted as proving that these drugs do not cause these two conditions.

But the flaw in the reasoning used here is simple: Short term studies can't discover potentially fatal cancers that take a decade or more to be Detectable.

The first study only lasted 2 years, which is far too short a time for the changes in pancreatic architecture discovered by Dr. Butler to result in overt pancreatitis. The study just published in the New England Journal of Medicine study only lasted three years. But it would be quite possible to draw the same conclusion about the safety of smoking cigarettes if you limited your study to a three year period.

Cancers of the pancreas take a long time to grow to where they are detectable, and by the time they are, they are almost always fatal. Pancreatic cancer is almost always symptom=free until it is too late for any treatment to keep the patient from dying within a few months.
The patients in Dr. Butler's study who took Januvia and died with small precancerous tumors in their pancreases and abnormal cells throughout their pancreatic tissue had no symptoms suggesting anything was wrong with them. Had they been subjects in the studies listed above, they would have been considered to not have cancer because the only cases of pancreatitis or pancreatic cancer which were evaluated in these studies were those that produced symptoms.

The reason it is so hard to detect early cancers of the pancreas--or the damaging structural changes that lead to pancreatitis is that there is no way to study the cells of a living pancreas without destroying it. That is why Dr. Butler was forced to study the pancreases of people who have died of head injuries.

Any study that assures you that these drugs are not damaging the pancreas which does not examine pancreatic tissue is not conclusive. Given how cancers progress, it will take 10 years or more for the pancreatic tumors these drugs are capable of growing to cause the epidemic of pancreatic cancer deaths that I fear is coming. By the time the deaths appear, it will be too late to do anything.

Until someone shows you 10 years worth of data that show no significant increase in cases of either pancreatitis or pancreatic cancer in people taking any incretin drug, be very skeptical of studies claiming they are safe.

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I was diagnosed with diabetes in 1998. Since then I've kept my A1cs in the 5.0-6.0% range using the techniques you'll find explained at The main Blood Sugar 101 Web Site, where you'll also find extensive discussion of the peer-reviewed research that backs up the statements you read here.

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